MYC c.212_214dup, p.(Leu71dup)

Reasoning

PM2 (absent or at extremely low frequency in population databases) is met at supporting strength. The variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (HostSeq genomes) — observed AF = 0 in three independent population datasets, well below the generic non-VCEP PM2 threshold of <0.1% and consistent across two exome releases plus an independent genome cohort. PM2 is applied at supporting strength per the SVI-calibrated generic framework (Tavtigian et al. 2018, PMID 28492532), rather than the original moderate assignment. Threshold artifacts considered: the variant is an in-frame 3-bp duplication (TGC) in a repetitive context (normalized description carries 5' shift = 5), so short-read under-ascertainment of such indels cannot be fully excluded; this caps confidence at moderate and limits the evidence to supporting strength, but does not negate the consistent absence.

Rule

Generic ACMG/AMP 2015 (PMID 25741868) PM2: absent or at extremely low frequency in population databases (<0.1% local non-VCEP threshold). Met: absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0; strength supporting (PMID 28492532).

Evidence considered

• gnomAD v2.1 exome: variant absent (0 alleles at 8-128750669-A-AGCT, GRCh37)
• gnomAD v4.1 exome: variant absent (0 alleles at chr8-127738423-A-AGCT, GRCh38)
• gnomAD-Canada v1.0 (HostSeq genomes): variant absent (0 carriers)
• Threshold: generic PM2 (AF < 0.1% in population databases; absence qualifies) per local non-VCEP gnomAD calibration; framework: Richards et al. 2015, PMID 25741868. Observed AF = 0 < 0.1%.
• PM2 supporting-strength calibration: SVI Bayesian framework, Tavtigian et al. 2018, PMID 28492532.

Still missing

• gnomAD results were captured only at the absence level (source_data empty in evidence.json): per-ancestry allele counts, total allele numbers (AN), and per-site coverage (DP) were not retrieved for gnomAD v2.1/v4.1 or gnomAD-Canada v1.0; absence is asserted from variant-page/API search_status=absent.
• Variant is an in-frame 3-bp duplication in a repetitive context (5' shift = 5); short-read alignment/annotation under-ascertainment cannot be fully excluded, so PM2 is applied at supporting strength only.
• PM2 applied at supporting strength only; no higher-strength population evidence available (e.g., large case-control absence data).

Sources

Reasoning

PM4 (Richards et al. 2015, PMID:25741868): 'Protein length changes as a result of in-frame insertions/deletions in a non-repeat region or stop-loss variants.' Verified consequence (Mutalyzer + VariantValidator, concordant; prefetch.json normalization): NM_002467.5:c.212_214dupTGC normalizes to c.212_214dup, an in-frame 3-nt duplication predicting NP_002458.2:p.(Leu71dup) in exon 2 (c.31-802) of the 454-aa MYC isoform. This changes protein length (+1 aa, 454 -> 455) and is not a frameshift, so no nonsense-mediated decay is triggered; SpliceAI max delta = 0.02 (evidence.json) predicts no splice impact, so the operative consequence is the protein-level in-frame length change. The duplicated residue is NOT in a repeat region: UCSC hg19 RepeatMasker and genomicSuperDups report no repeat element and no segmental duplication over chr8:128,750,500-128,750,900 (variant at g.128750675_128750677dup); sequence-level inspection of NM_002467.5 shows only a marginal 6-nt 'GCT GCT' tandem (c.208-213) at the site, no homopolymer or low-complexity tract at the duplicated residue. The residue lies in the MYC N-terminal transactivation domain (TAD), immediately N-terminal to the conserved phosphodegron region (T58/S62 in the 439-aa numbering; T73/S77 in the 454-aa isoform), a functionally important regulatory region. No MYC-specific VCEP/CSPEC exists (cspec found=false; framework_mode=generic_acmg), so the generic ACMG/AMP 2015 definition applies at default moderate strength. PM4 met.

Rule

PM4: in-frame insertion/deletion in a non-repeat region causing protein length change, or stop-loss variant (Richards et al. 2015, PMID:25741868)

Evidence considered

• Normalized consequence (prefetch.json, Mutalyzer + VariantValidator concordant): NM_002467.5:c.212_214dupTGC -> c.212_214dup -> NP_002458.2:p.(Leu71dup); in-frame single-residue duplication; exon 2 (c.31-802); protein length +1 aa.
• SpliceAI (evidence.json): max delta score 0.02, DS_AG 0.02 - no predicted splice impact; operative consequence is the in-frame protein change, not altered splicing.
• UCSC hg19 RepeatMasker and genomicSuperDups (chr8:128,750,500-128,750,900): no repeat element and no segmental duplication overlapping the variant site (g.128750675_128750677dup).
• Sequence-level inspection of NM_002467.5 (NCBI): duplicated unit TGC at c.212-214 within a short 'GCT GCT' tandem (c.208-213); no homopolymer/low-complexity tract at the duplicated residue; residue located in the N-terminal transactivation domain adjacent to the conserved phosphodegron region (T58/S62 equivalents).

Still missing

• No MYC-specific VCEP/CSPEC or gene-specific PM4 calibration exists; generic ACMG/AMP 2015 (PMID:25741868) applied at default moderate strength.
• No functional or experimental data for p.(Leu71dup) are present in the case bundle (OncoKB: no variant-specific reviewed functional evidence, 'Unknown Oncogenic Effect'); PM4 is applied on consequence/sequence context alone.

Sources

Reasoning

PS4 requires the variant to be significantly enriched in affected individuals compared with controls (case-control study with odds ratio / statistical significance, or strong variant-specific functional data under SVI-strength adjustments). No such evidence exists for NM_002467.5:c.212_214dupTGC (MYC p.(Leu71dup)): the literature pass returned 0 PMIDs across all evidence sources; ClinVar has no record and therefore no case-level submissions; OncoKB provides no variant-specific reviewed functional evidence (Unknown Oncogenic Effect); and the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (no population/control frequency). The only variant occurrence in the bundle is a COSMIC somatic entry (COSV99419973, n=2), which is somatic cancer occurrence data without controls or statistics and is not case-control enrichment evidence; it also lacks a source_registry key and cannot be cited. PS4 is affirmatively not met.

Rule

Generic ACMG/AMP 2015 PS4 - prevalence of variant in affected individuals significantly increased compared with controls (generic_acmg_combination_rules; Richards et al. 2015, PMID:25741868)

Evidence considered

• generic_acmg_combination_rules: PS4 requires significant enrichment of the variant in affected individuals vs controls (ACMG/AMP 2015, Richards et al., PMID:25741868)
• clinvar: no ClinVar record for the exact variant - no case-level submissions or enrichment data
• oncokb: no variant-specific reviewed functional evidence (classification 'Unknown Oncogenic Effect', is_variant_specific=false)
• gnomad_v2 / gnomad_v4 / gnomad_canada: variant absent from germline population databases - no enrichment signal, consulted as prevalence/control-frequency context

Still missing

• No case-control or affected-vs-control prevalence study exists for this variant (literature_pass total_pmids = 0).
• No variant-specific functional assay evidence (e.g., validated oncogenic/functional readout) that could support PS4 at reduced strength.
• Only variant occurrence is COSMIC COSV99419973 (somatic n=2); somatic occurrence without controls, OR, or statistics cannot meet PS4 and is not citable (no source_registry key).

Sources

Reasoning

No computational evidence supports a deleterious effect. Splice path: SpliceAI max delta score is 0.02 (DS_AG 0.02, DS_AL 0.01, DS_DG 0.01, DS_DL 0.00) with the nearest predicted splice-site changes 172-384 nt away; this is far below the 0.2 high-sensitivity splice-altering threshold (Jaganathan et al. 2019, Nat Genet, PMID 30661751), so no splice-impact evidence supports PP3. Missense path: REVEL and BayesDel were skipped at prefetch ('not snv or no coords') because the variant is a non-SNV in-frame duplication (p.Leu71dup); aGVGD is likewise not applicable. No calibrated in-silico evidence path is available or applicable for this variant class, therefore PP3 is not met. Governing framework: generic ACMG/AMP 2015 (PMID 25741868); no CSPEC/VCEP or local gene-specific framework exists for MYC (final_classification_framework.json: generic_acmg_fallback).

Still missing

• Missense in-silico predictor scores (REVEL/BayesDel/aGVGD) are not available and are not applicable to this in-frame duplication (prefetch skipped both REVEL and BayesDel: 'not snv or no coords'); only the splice-impact path could be evaluated.
• BayesDel currently has no verified published threshold available to this pipeline, so even a raw BayesDel score would be treated as insufficiently calibrated for PP3/BP4.

Sources

Reasoning

Per this group's rule, PP5 may only be triggered by an exact-variant ClinVar expert-panel classification of Pathogenic or Likely Pathogenic (3-star expert panel); ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger PP5. The exact variant NM_002467.5:c.212_214dupTGC has NO ClinVar record at all (variation_ids empty, no submissions, no review status across all search formulations in prefetch.json). No expert-panel classification exists, so the PP5 trigger is absent. Not met.

Rule

PP5 - exact-variant ClinVar expert-panel (3-star) classification as Pathogenic/Likely Pathogenic only; ordinary laboratory submissions, aggregate labels, and non-expert assertions never trigger (group rule; clinvar registry source)

Evidence considered

• clinvar: exact variant absent from ClinVar (variation_ids = [], submissions = [], review_status = '') - no expert-panel classification to trigger PP5
• generic_acmg_combination_rules: PP5 as supporting-level ClinVar-derived criterion within generic ACMG/AMP 2015

Still missing

• No ClinVar record exists for this exact variant; PP5 can only be reconsidered if ClinVar later gains a 3-star expert-panel Pathogenic/Likely Pathogenic entry for the exact variant (re-audit).

Sources

Reasoning

BA1 (allele frequency >1% in a large reference population, stand-alone benign) is not met. The variant NM_002467.5:c.212_214dupTGC is absent from gnomAD v2.1 (exomes, GRCh37), gnomAD v4.1 (exomes, GRCh38), and gnomAD-Canada v1.0 (HostSeq genomes, GRCh38) — observed allele frequency is 0 in every population dataset queried, three or more orders of magnitude below the generic non-VCEP BA1 threshold of >1%. No disease-prevalence or penetrance argument could place an absent variant near BA1. COSMIC reports 2 somatic cancer observations (COSV99419973), but somatic tumor counts are not germline population frequency and were excluded. Generic ACMG/AMP fallback applies because no ClinGen CSPEC/VCEP or local gene-specific framework exists for MYC (framework_mode=generic_acmg).

Rule

Generic ACMG/AMP 2015 (PMID 25741868) BA1: allele frequency >1% in a large reference population is stand-alone benign. Not met: variant absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (AF = 0).

Evidence considered

• gnomAD v2.1 exome: variant absent (search_status=absent, 0 alleles reported at 8-128750669-A-AGCT, GRCh37)
• gnomAD v4.1 exome: variant absent (search_status=absent, 0 alleles reported at chr8-127738423-A-AGCT, GRCh38)
• gnomAD-Canada v1.0 (HostSeq genomes): variant absent (0 carriers)
• COSMIC COSV99419973: 2 somatic observations only; somatic data excluded from germline allele-frequency evaluation
• Threshold: generic ACMG/AMP 2015 BA1 (AF > 1% in a large reference population) per local generic non-VCEP gnomAD calibration; framework: Richards et al. 2015, PMID 25741868. Observed AF = 0, far below 1%.

Sources

Reasoning

BS1 (allele frequency greater than expected for the disorder) is not met. The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (observed AF = 0 in all three datasets), far below the generic non-VCEP BS1 threshold of >0.3%. Even under the most permissive modeling of a MYC-associated germline phenotype (dominant, incompletely penetrant, adult onset; no prevalence estimate is established for MYC in this case), an observed AF of 0 cannot exceed the expected disease-allele frequency. No BA1/BS1 threshold artifact favors the variant: absence is consistent across two independent exome releases and an independent genome cohort.

Rule

Generic ACMG/AMP 2015 (PMID 25741868) BS1: allele frequency greater than expected for the disorder. Not met: observed AF = 0 (<0.3% local threshold).

Evidence considered

• gnomAD v2.1 exome: variant absent (0 alleles)
• gnomAD v4.1 exome: variant absent (0 alleles)
• gnomAD-Canada v1.0: variant absent (0 carriers)
• MYC germline disease prevalence/penetrance not established in this case (pvs1_gene_context disease names derive from literature hits on other genes), so no expected disease-allele frequency could be modeled; absence alone fails BS1
• Threshold: generic BS1 (AF greater than expected for the disorder; local non-VCEP calibration >0.3%) per Richards et al. 2015, PMID 25741868. Observed AF = 0, below 0.3%.

Sources

Reasoning

BS2 (observed in a healthy adult: homozygous for recessive, or heterozygous with full penetrance expected at an early age for dominant disorders) is not met. The variant has zero observations in gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (no heterozygotes, no homozygotes), and is absent from ClinVar (no germline submissions, no carrier/frequency data). There is therefore no healthy-adult observation of any kind. In addition, no established MYC germline disorder with known prevalence and penetrance is available in this case bundle, so the dominant full-penetrance-at-early-age clause of BS2 could not be evaluated even if carriers existed; the zero-observation result independently fails BS2. No curated unaffected-carrier or case-control dataset is present (literature_pass total_pmids=0).

Rule

Generic ACMG/AMP 2015 (PMID 25741868) BS2: observed in a healthy adult (homozygous for recessive, or heterozygous with full penetrance expected at an early age for dominant). Not met: zero observations in gnomAD v2.1/v4.1, gnomAD-Canada v1.0, and ClinVar.

Evidence considered

• gnomAD v2.1 exome: variant absent — 0 heterozygotes, 0 homozygotes
• gnomAD v4.1 exome: variant absent — 0 heterozygotes, 0 homozygotes
• gnomAD-Canada v1.0: variant absent — 0 carriers
• ClinVar: variant absent (no submissions); no allele-frequency, homozygote, or healthy-carrier data available
• MYC germline context: no verified dominant/recessive disease model or penetrance estimate in this case; zero observations fail BS2 regardless of model

Still missing

• No curated clinical unaffected-carrier or case-control dataset available in this case to directly assess BS2 (literature_pass found 0 PMIDs).
• No established MYC germline disorder prevalence/penetrance in the case bundle (pvs1_gene_context disease context derives from literature hits on other genes: FBXW7, PMP22, APC, FOXP3, SMARCA4), so BS2 disease-model assumptions (expected carrier rate, penetrance at early age) are unverified.

Sources

Reasoning

BP3 (Richards et al. 2015, PMID:25741868): 'In-frame insertions/deletions in a repeat region without known function.' The variant is an in-frame 3-nt duplication (p.(Leu71dup)), satisfying the in-frame-indel premise, but the two remaining conditions fail. (1) Repeat region: UCSC hg19 RepeatMasker and genomicSuperDups report no repeat element/segmental duplication at the site (chr8:128,750,500-128,750,900), and sequence inspection shows only a marginal 6-nt 'GCT GCT' tandem (c.208-213) with no homopolymer or low-complexity tract at the duplicated residue - this is not a canonical repeat region of the type BP3 targets (homopolymer/STR/low-complexity tracts). (2) Known function: the duplicated residue lies in the MYC N-terminal transactivation domain immediately adjacent to the conserved phosphodegron region (T58/S62 equivalents, a well-characterized regulated-degradation hotspot in lymphoma biology), so the region is not 'without known function'. Because the 'repeat region' and 'without known function' clauses are both unsatisfied, BP3 is not met.

Rule

BP3: in-frame insertions/deletions in a repeat region without known function (Richards et al. 2015, PMID:25741868)

Evidence considered

• Normalized consequence (prefetch.json, Mutalyzer + VariantValidator concordant): in-frame single-residue duplication p.(Leu71dup) - in-frame indel premise of BP3 satisfied.
• UCSC hg19 RepeatMasker and genomicSuperDups (chr8:128,750,500-128,750,900): no repeat element, no segmental duplication at the variant site; sequence inspection shows only a marginal 6-nt 'GCT GCT' tandem, no homopolymer/STR/low-complexity tract at the duplicated residue.
• Established MYC biology (general knowledge, not from case sources): the N-terminal TAD and its conserved phosphodegron region (T58/S62 equivalents) have known regulatory function, so BP3's 'without known function' clause fails.
• SpliceAI (evidence.json): max delta 0.02 - no splice impact; variant effect is confined to the in-frame protein change (no alternative splicing mechanism that would change BP3's repeat-region assessment).

Still missing

• Whether the short GCT-rich tandem at c.208-213 qualifies as a 'repeat region' under BP3 is not resolved by any gene-specific specification; UCSC hg19 RepeatMasker reports no repeat element at the site.
• No curated repeat/low-complexity annotation for the MYC aa 56-71 region is present in the case bundle.

Sources

Reasoning

BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product (generic ACMG/AMP 2015, PMID 25741868). Only a single computational line is available: SpliceAI max delta 0.02. However, this variant lies ~181 nt into exon 2 (exon 2 spans c.31-802 of NM_002467.5) with predicted splice-site changes 172-384 nt away, i.e. outside canonical splice regions, where a low SpliceAI score is the expected default rather than affirmative evidence of no impact. The missense in-silico path (REVEL/BayesDel/aGVGD) does not apply to this non-SNV in-frame duplication and no scores were generated, and no conservation/evolutionary in-silico scores for in-frame duplications are available. A single low SpliceAI score therefore does not satisfy BP4's multiple-line requirement, and BP4 is not met.

Still missing

• Only one computational line (SpliceAI) could be evaluated for this variant; the 'multiple lines' requirement of BP4 cannot be satisfied because no missense in-silico predictor (REVEL/BayesDel/aGVGD) applies to in-frame duplications and no conservation-based scores for this variant class are available.
• No VCEP/gene-specific PP3/BP4 lookup material exists for MYC that could pre-assign BP4 (vcep_materials.json: no cspec url, no files found).

Sources

Reasoning

Per this group's rule, BP6 may only be triggered by an exact-variant ClinVar expert-panel classification of Benign or Likely Benign (3-star expert panel); ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger BP6. The exact variant NM_002467.5:c.212_214dupTGC has NO ClinVar record at all (variation_ids empty, no submissions, no review status). No expert-panel benign classification exists, so the BP6 trigger is absent. Not met.

Rule

BP6 - exact-variant ClinVar expert-panel (3-star) classification as Benign/Likely Benign only; ordinary laboratory submissions, aggregate labels, and non-expert assertions never trigger (group rule; clinvar registry source)

Evidence considered

• clinvar: exact variant absent from ClinVar (variation_ids = [], submissions = [], review_status = '') - no expert-panel benign classification to trigger BP6
• generic_acmg_combination_rules: BP6 as supporting-level ClinVar-derived criterion within generic ACMG/AMP 2015

Still missing

• No ClinVar record exists for this exact variant; BP6 can only be reconsidered if ClinVar later gains a 3-star expert-panel Benign/Likely Benign entry for the exact variant (re-audit).

Sources

Reasoning

PS2 requires a documented de novo occurrence in a proband with both biological parents tested and parental identity confirmed. This case bundle contains no proband clinical or phenotype data, no parental testing results, and no documented de novo observation for MYC c.212_214dup (p.Leu71dup). ClinVar has no entry for this variant (variation_ids: [], 'This variant is absent from ClinVar') and the literature pass recovered 0 PMIDs, so no curated de novo report is available from any source. Evidence is insufficient; the criterion cannot be assessed.

Rule

PS2 (Richards et al. 2015, PMID 25741868): de novo occurrence in a proband with confirmed parental identity, strong pathogenic evidence.

Evidence considered

• clinvar: variant absent from ClinVar; no curated de novo report or parental testing data
• generic_acmg_combination_rules: governing generic ACMG/AMP 2015 fallback framework (PMID 25741868) applied because no MYC CSPEC/VCEP or local custom framework exists

Still missing

• No proband clinical/phenotype data present in the case bundle
• No parental testing or parental identity confirmation data
• No documented de novo occurrence for c.212_214dup (p.Leu71dup) in any case source

Sources

Reasoning

No CSPEC/VCEP specification exists for MYC (cspec.found=false, gene_vcep_dir=null), so the generic ACMG/AMP 2015 framework (Richards et al., PMID 25741868) governs. PS3 requires well-established functional studies showing a deleterious effect on the gene or gene product. The case bundle contains no variant-specific functional assay for NM_002467.5:c.212_214dupTGC (p.Leu71dup): OncoKB explicitly reports no variant-specific reviewed functional evidence (classification 'Unknown Oncogenic Effect', is_variant_specific=false, not_reviewed=true); COSMIC lists the variant in somatic cancers only (COSV99419973, n=2), which is a curated catalogue entry without an assay readout or controls and cannot constitute a functional study; SpliceAI (max delta 0.02) is an in silico predictor, not a functional assay and not applicable to PS3. literature_pass returned 0 PMIDs, fulltext_map.json is empty, and no publications directory exists, so no functional study could be retrieved. Functional evidence is therefore insufficient; PS3 is not_assessed.

Rule

PS3 (Richards et al. 2015, PMID 25741868; generic ACMG/AMP fallback): well-established functional studies show a deleterious effect on the gene or gene product; default strength strong (per-criterion strength calibration per SVI guidance not applicable here because no functional evidence exists)

Evidence considered

• generic_acmg_combination_rules: Richards et al. 2015 ACMG/AMP framework (PMID 25741868) — governing rule basis for PS3 (well-established functional studies show a deleterious effect); applied because no VCEP/CSPEC exists for MYC
• oncokb: OncoKB MYC/L71dup entry reports no variant-specific reviewed functional evidence (Unknown Oncogenic Effect, not_reviewed=true) — no assay support for a deleterious effect
• clinvar: variant absent from ClinVar (no_result) — no curated functional evidence submissions
• spliceai: max delta score 0.02 — in silico splice prediction only; not a functional assay and cannot satisfy PS3

Still missing

• No validated variant-specific functional assay data for p.Leu71dup (e.g., MYC transactivation, transformation, or MYC/MAX DNA-binding assays) available in the case bundle
• No functional study retrievable from the literature (literature_pass 0 PMIDs, empty fulltext_map, no publications directory)

Sources

Reasoning

PM3 (Richards et al. 2015, PMID 25741868) requires a disorder with autosomal recessive inheritance in which the variant is detected in trans with a pathogenic variant in an affected individual. None of the required components can be evaluated from this case bundle: (1) no affected proband carrying NM_002467.5:c.212_214dup is identified anywhere in the collected sources (ClinVar has no record; literature_pass returned 0 PMIDs); (2) no second (pathogenic) variant on the homologous allele exists to phase against — pm5_candidates harvested 0 comparator candidates; (3) no phase (trans/cis) information was collected from any source; (4) no autosomal recessive MYC germline disorder is established — pvs1_gene_context lists no inheritance mode (inheritance: []) and its supporting papers concern non-MYC genes (FBXW7, PMP22, APC, FOXP3, SMARCA4). The variant is absent from gnomAD v2.1/v4.1/Canada and has only somatic observations (COSMIC n=2), which are not germline allelic evidence. Because the deficiency is total absence of proband/family/phase data rather than contrary evidence, the criterion is returned not_assessed with the specific gaps listed.

Rule

Generic ACMG/AMP 2015 (Richards et al., PMID 25741868): PM3 — 'For recessive disorders, detected in trans with a pathogenic variant' (moderate, pathogenic direction)

Evidence considered

• clinvar: variant absent (search_status no_result); no submissions exist, so no proband-level or phase (in-trans) observation is recorded anywhere
• pm5_candidates: 0 comparator candidates collected (total_candidates_seen: 0), confirming no pathogenic variant is available on the homologous allele for trans evaluation
• pvs1_gene_context: no MYC inheritance mode established (inheritance: []); disease_names references a FBXW7 disorder and the 5 supporting papers concern FBXW7/PMP22/APC/FOXP3/SMARCA4, not MYC germline disease — the recessive-disease prerequisite of PM3 is unmet/unverifiable
• gnomad_v2 / gnomad_v4 / gnomad_canada: variant absent from all three population datasets; no carrier observations that could inform allelic context
• generic_acmg_combination_rules: governing fallback framework is Richards et al. 2015 (PMID 25741868), which defines PM3 as 'For recessive disorders, detected in trans with a pathogenic variant'

Still missing

• No affected proband identified with NM_002467.5:c.212_214dup (no ClinVar record, no literature, no case-level data in bundle)
• No pathogenic variant on the homologous allele identified (pm5_candidates: 0) against which trans phase could be established
• No phase information (parental genotypes, single-nucleotide/phased read data, family segregation) collected for this variant
• No established autosomal recessive MYC germline disorder or inheritance mode (pvs1_gene_context inheritance list is empty; supporting literature concerns other genes)

Sources

Reasoning

PM6 requires a de novo occurrence without confirmed parental identity (assumed de novo). No proband, parental, or sibling testing data are present anywhere in the case bundle, and no de novo observation exists in ClinVar (variant absent) or in the literature pass (0 PMIDs). Evidence is insufficient; the criterion cannot be assessed.

Rule

PM6 (Richards et al. 2015, PMID 25741868): assumed de novo occurrence without confirmation of parental identity, moderate pathogenic evidence.

Evidence considered

• clinvar: variant absent from ClinVar; no de novo or parental testing observations
• generic_acmg_combination_rules: governing generic ACMG/AMP 2015 fallback framework (PMID 25741868)

Still missing

• No proband or parental testing data in the case bundle
• No de novo occurrence documented for c.212_214dup in any case source
• No assumption-of-de-novo basis (e.g., proband phenotype, maternity/paternity) available

Sources

Reasoning

PP1 requires co-segregation of the variant with disease in multiple affected family members. The case bundle contains no pedigree, family history, or segregation data, and no affected relatives were tested for c.212_214dup. ClinVar has no entry for the variant and the literature pass recovered 0 PMIDs, so no published segregation observation exists. Evidence is insufficient; the criterion cannot be assessed.

Rule

PP1 (Richards et al. 2015, PMID 25741868): co-segregation of the variant with disease in multiple affected family members, supporting pathogenic evidence.

Evidence considered

• clinvar: variant absent from ClinVar; no segregation observations
• generic_acmg_combination_rules: governing generic ACMG/AMP 2015 fallback framework (PMID 25741868)

Still missing

• No pedigree or family history data in the case bundle
• No affected family members genotyped for c.212_214dup
• No segregation counts (informative meioses) available from any source

Sources

Reasoning

PP4 requires the variant to be found in a proband with a phenotype or family history highly specific for a gene with a single genetic etiology. The case bundle contains no proband phenotype data at all (no HPO terms, no clinical description, no family history) in case_summary.json, so phenotype specificity cannot be evaluated. In addition, there is no established MYC germline disease specification (no CSPEC/VCEP exists; cspec found=false) to anchor a highly-specific-phenotype argument, and OncoKB's gene-level context describes only somatic cancer alteration (rearrangement, amplification, overexpression), which does not establish a germline phenotype for MYC. Evidence is insufficient; adjudication requires the proband's clinical phenotype.

Rule

Generic ACMG/AMP 2015 PP4 - phenotype or family history highly specific for a gene with a single genetic etiology (generic_acmg_combination_rules)

Evidence considered

• generic_acmg_combination_rules: PP4 requires phenotype or family history highly specific for a gene with a single genetic etiology
• case_summary.json: no phenotype/clinical section was collected for this case
• clinvar: no ClinVar record, so no phenotype-linked case description is available
• oncokb: only somatic cancer gene-level context for MYC; does not support germline phenotype specificity

Still missing

• No proband phenotype data (HPO terms / clinical description / family history) is present in the case bundle - must be supplied by human review of the clinical record.
• No established MYC germline phenotype specification exists (no CSPEC/VCEP) to anchor a PP4 highly-specific-phenotype argument.

Sources

Reasoning

No CSPEC/VCEP specification exists for MYC, so the generic ACMG/AMP 2015 framework (Richards et al., PMID 25741868) governs. BS3 requires well-established functional studies showing no damaging effect on the gene or gene product. The only variant-level 'no-impact' signal in the bundle is SpliceAI (max delta score 0.02), which is an in silico splice prediction, not a functional study, and is explicitly insufficient for BS3 under ACMG/AMP. OncoKB provides no variant-specific functional data (Unknown Oncogenic Effect, not reviewed); the variant is absent from ClinVar; literature_pass returned 0 PMIDs and no full-text articles are available. No well-established functional assay demonstrating a lack of damaging effect (e.g., MYC transactivation/transformation assays with proper controls) exists in the evidence bundle. Functional evidence is therefore insufficient; BS3 is not_assessed.

Rule

BS3 (Richards et al. 2015, PMID 25741868; generic ACMG/AMP fallback): well-established functional studies show no damaging effect on the gene or gene product; default strength supporting (benign)

Evidence considered

• generic_acmg_combination_rules: Richards et al. 2015 ACMG/AMP framework (PMID 25741868) — governing rule basis for BS3 (well-established functional studies show no damaging effect); applied because no VCEP/CSPEC exists for MYC
• spliceai: SpliceAI max delta score 0.02 (DS_AG 0.02, DS_AL 0.01, DS_DG 0.01, DS_DL 0.0) — in silico prediction consulted; not a functional study, insufficient alone for BS3
• oncokb: OncoKB MYC/L71dup entry reports no variant-specific reviewed functional evidence — no functional data demonstrating lack of damaging effect
• clinvar: variant absent from ClinVar — no curated benign functional evidence submissions

Still missing

• No well-established functional assay (with controls) demonstrating p.Leu71dup has no damaging effect on MYC function
• SpliceAI (in silico) is the only no-impact signal available and cannot substitute for a functional study for BS3

Sources

Reasoning

BS4 requires observed non-segregation of the variant with disease in affected family members (e.g., variant present in unaffected individuals or absent in affected individuals). No segregation or family testing data exist for c.212_214dup in any case source, and absence of data cannot be used as non-segregation evidence. Evidence is insufficient; the criterion cannot be assessed.

Rule

BS4 (Richards et al. 2015, PMID 25741868): non-segregation with disease in affected family members, strong benign evidence.

Evidence considered

• clinvar: variant absent from ClinVar; no non-segregation observations
• generic_acmg_combination_rules: governing generic ACMG/AMP 2015 fallback framework (PMID 25741868)

Still missing

• No family segregation testing data in the case bundle
• No observations of the variant in unaffected relatives or absence in affected relatives
• Non-segregation cannot be inferred from the absence of any family data

Sources

Reasoning

BP2 (Richards et al. 2015, PMID 25741868) requires either observation in trans with a pathogenic variant for a fully dominant disorder, or observation in cis with a pathogenic variant in any inheritance pattern. No component is assessable from this bundle: there is no second pathogenic variant on either allele, no phase (trans or cis) information of any kind, no proband/family data, and no fully dominant MYC germline disorder established (pvs1_gene_context provides no inheritance mode and its supporting papers concern other genes). The variant is absent from ClinVar and from gnomAD v2.1/v4.1/Canada. Because the deficiency is total absence of phase/allelic data rather than contrary evidence, the criterion is returned not_assessed with the specific gaps listed.

Rule

Generic ACMG/AMP 2015 (Richards et al., PMID 25741868): BP2 — 'Observed in trans with a pathogenic variant for a fully dominant disease/disorder; OR observed in cis with a pathogenic variant in any inheritance pattern' (supporting, benign direction)

Evidence considered

• clinvar: variant absent (search_status no_result); no submission records any cis/trans phase observation with a pathogenic variant
• pm5_candidates: 0 comparator candidates — no pathogenic variant exists in the collected evidence with which a cis or trans configuration could be demonstrated
• pvs1_gene_context: no MYC inheritance mode established (inheritance: []); no fully dominant MYC germline disorder exists in the collected literature (supporting papers concern FBXW7/PMP22/APC/FOXP3/SMARCA4), failing the fully-dominant prerequisite of BP2
• gnomad_v2 / gnomad_v4 / gnomad_canada: variant absent from all three population datasets; no observations that could contribute allelic context
• generic_acmg_combination_rules: governing fallback framework is Richards et al. 2015 (PMID 25741868), which defines BP2 as 'Observed in trans with a pathogenic variant for a fully dominant disease/disorder; OR observed in cis with a pathogenic variant in any inheritance pattern'

Still missing

• No phase information (trans or cis) available for this variant relative to any other variant
• No second (pathogenic) variant identified on either allele to establish a cis or trans configuration
• No affected proband or family observation recorded for this variant (ClinVar absent, literature_pass 0 PMIDs)
• No established fully dominant MYC germline disorder or inheritance mode to anchor the in-trans arm of BP2

Sources

Reasoning

BP5 requires evidence of an alternative molecular basis for the disease in the proband (e.g., a distinct pathogenic variant in another gene, or an alternate variant/haplotype explaining the phenotype). The case bundle contains no genotype data beyond the index variant: no second-variant analysis, no multigene panel results, no phasing/haplotype information, and no proband clinical context in which an alternative cause could be evaluated. Evidence is insufficient to either meet or exclude BP5; the deciding data would have to come from outside the bundle (human review of the testing report).

Rule

Generic ACMG/AMP 2015 BP5 - alternative molecular basis for the disease exists in the proband (generic_acmg_combination_rules)

Evidence considered

• generic_acmg_combination_rules: BP5 requires a distinct alternative molecular basis for the disease in the proband
• case_summary.json / evidence.json: no second-variant, panel, or genotype data available for this case

Still missing

• No data on any alternative causal variant (second variant in another gene / alternate molecular basis) is present in the bundle.
• No proband genotype, phasing, or multigene-panel results were collected; required for BP5 evaluation.

Sources